Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer

Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex. In cancer cells, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression.     

Evidence for an instructive mechanism of de novo methylation in cancer cells

DNA methylation has a role in the regulation of gene expression during normal mammalian development but can also mediate epigenetic silencing of CpG island genes in cancer and other diseases. Many individual genes (including tumor suppressors) have been shown to undergo de novo methylation in specific tumor types, but the biological logic inherent in this process is not understood. To decipher this mechanism, we have adopted a new approach for detecting CpG island DNA methylation that can be used together with microarray technology. Genome-wide analysis by this technique demonstrated that tumor-specific methylated genes belong to distinct functional categories, have common sequence motifs in their promoters and are found in clusters on chromosomes. In addition, many are already repressed in normal cells. These results are consistent with the hypothesis that cancer-related de novo methylation may come about through an instructive mechanism.     

Reptile distribution may identify terrestrial islands for conservation: the Levant’s ‘Arava Valley as a model

Widely accepted major criteria for biodiversity hotspots that deserve conservation include species richness, endemism and threat. Proving that a taxon is endemic to a given area is more difficult, and therefore expensive, with animals than with plants because of the difficulty to prove absence outside the known distribution. Seeking a cost-efficient practical method to show animal endemism while funds necessary for conventional demonstration of endemism are lacking, we argued that when the known distribution of a suspected endemic taxon coincides with an eco-geographically isolated area, e.g. island, its exclusivity to that area is more credible. We selected a model site containing suspected endemics, the ‘Arava depression (altitude - 400–0 m) between arid southern Israel and southern Jordan. A search of the literature and collections found at least 23 animal taxa endemic to the ‘Arava, to the adjacent Dead Sea basin sharing the depression, or to both. We assessed the level of isolation of the ‘Arava depression by statistically analysing the geographical distribution of taxa (species or subspecies) of one selected well researched model group, Squamata (lizards and snakes). In northern Israel and Jordan the squamate faunas of the two countries are very similar. In contrast in the south where the ‘Arava intervenes, the two faunas greatly differ. The ‘Arava both constitutes a partial barrier and is partly isolated. Hence its apparent endemics are likely real endemics, inviting conservation of the area. The more so since the ‘Arava is also an arena of much research and education. Our methodology may serve worldwide to identify semi-isolated terrestrial areas for conservation.